The development of primary drug resistance and the associated phenomenon of multidrug resistance (MDR) in relapsed cancer (1), are major determinants of treatment failure. The therapeutic means to circumvention of MDR is under intensive experimental study using a variety of tumor cell systems that express the phenotype. It is known that MDR cells accumulate less drug than parental, sensitive tumor cells due to the enhanced expression of an efflux pump, termed P-glycoprotein (see reviews 2,3). Compounds have been identified which can sensitize MDR cells to anticancer drugs in combination treatments (4-8). These modulators of drug resistance, typically weak cytotoxic agents without antitumor activity by themselves, enhance the intracellular drug concentration.
The first identified modulators of MDR in cultured cells were the calcium channel blocker verapamil (19) and the calmodulin inhibitor trifluorperazine (20). Since then, numerous other diverse compounds, such as reserpine (5), non-antitumor monomeric vinca alkaloids (14) and ADM analogs (13) have been shown to sensitize MDR cells to the anticancer drugs of the phenotype.
Generally, the known modulators sensitize MDR cells to all of the drugs in the resistance profile, with less pronounced or nonexistent effects on parental cells.